Use of antiviral drugs to treat HIV infection is often limited by the inability of the compounds to access sites of infection or by drug toxicity. In this regard, the brain provides a sanctuary for HIV. Three barriers can confound treatment of virus within the brain: the blood-brain barrier at the capillary endothelium, the blood-CSF barrier at the choroid plexus and the plasma membranes of the glial cells that harbor HIV. With regard to poor blood-brain barrier penetration of HIV protease inhibitors, our experiments with isolated rat and pig brain capillaries indicate that the ATP-driven drug export pumps, p-glycoprotein and Mrp2, are important impediments to penetration in that both ritonavir and saquinavir interact with these transporters. Our recent in vitro and in vivo experiments with animal models suggest three strategies for circumventing this barrier: specific inhibition of p-glycoprotein activity using PSC833, transient opening of brain capillary tight junctions with alkyl glycerols and rapid and transient reduction in p-glycoprotein transport function signaled through the brain?s innate immune response. In contrast to the blood-brain barrier, it is still not clear by what mechanisms HIV protease inhibitors are cleared from the CSF. However, experiments with isolated choroid plexus from mice and rats indicate specific uptake of saquinavir from CSF. Finally, Our initial experiments indicate expression of p-glycoprotein and several Mrp family members in plasma membranes from astrocytes and microglia. As in other tissues, expression of these transporters appears to be transcriptionally regulated by multiple factors including, cytokines.